Human T-cell lymphotropic virus type 1 Tax represses c-Myb-dependent transcription through activation of the NF-kappaB pathway and modulation of coactivator usage.
The proto-oncogene c-myb is essential for a controlled balance between cell growth and differentiation. Aberrant c-Myb activity has been reported for numerous human cancers, and enforced c-Myb transcription can transform cells of lymphoid origin by stimulating cellular proliferation and inhibiting apoptotic pathways. Here we demonstrate that activation of the NF-kappaB ... pathway by the HTLV-1 Tax protein leads to transcriptional inactivation of c-Myb. This conclusion was supported by the fact that Tax mutants unable to stimulate the NF-kappaB pathway could not inhibit c-Myb transactivating functions. In addition, inhibition of Tax-mediated NF-kappaB activation by coexpression of IkappaBalpha restored c-Myb transcription, and Tax was unable to block c-Myb transcription in a NEMO knockout cell line. Importantly, physiological stimuli, such as signaling with the cellular cytokines tumor necrosis factor alpha, interleukin 1 beta (IL-1beta), and lipopolysaccharide, also inhibited c-Myb transcription. These results uncover a new link between extracellular signaling and c-Myb-dependent transcription. The mechanism underlying NF-kappaB-mediated repression was identified as sequestration of the coactivators CBP/p300 by RelA. Interestingly, an amino-terminal deletion form of p300 lacking the C/H1 and KIX domains and unable to bind RelA retained the ability to stimulate c-Myb transcription and prevented NF-kappaB-mediated repression.
Mesh Terms:
Animals, Cell Differentiation, Cell Division, Cell Line, DNA-Binding Proteins, E1A-Associated p300 Protein, Enzyme Activation, Gene Deletion, Gene Products, tax, I-kappa B Proteins, Immunoblotting, Interleukin-1, Ligases, Luciferases, Mice, Mice, Knockout, Microscopy, Fluorescence, Mutation, NF-kappa B, Nuclear Proteins, Phenotype, Plasmids, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-myb, Rabbits, Reticulocytes, Signal Transduction, Trans-Activators, Transcription, Genetic, Transcriptional Activation, Transfection
Animals, Cell Differentiation, Cell Division, Cell Line, DNA-Binding Proteins, E1A-Associated p300 Protein, Enzyme Activation, Gene Deletion, Gene Products, tax, I-kappa B Proteins, Immunoblotting, Interleukin-1, Ligases, Luciferases, Mice, Mice, Knockout, Microscopy, Fluorescence, Mutation, NF-kappa B, Nuclear Proteins, Phenotype, Plasmids, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-myb, Rabbits, Reticulocytes, Signal Transduction, Trans-Activators, Transcription, Genetic, Transcriptional Activation, Transfection
Mol. Cell. Biol.
Date: Nov. 01, 2001
PubMed ID: 11585920
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